Sincere appreciation is extended to NB Alliance UK for inviting me to attend this meeting and providing the travel funds.

Tubingen Town Hall

This was the fourth meeting in a series on pediatric solid tumors and the first time the focus was on neuroblastoma. It was hosted at the Children’s Hospital (Kinderklinik) in the beautiful old city of Tübingen, which is home to the top ranked German University founded in 1477. The 17 hospitals in Tübingen associated with the university treat 66,000 in-patients and 200,000 out-patients on an annual basis. This unique meeting was attended by approximately 130 scientists, clinicians, surgeons, and a few parents from more than 30 countries. The festival Fasnet happened to be underway and on Thursday the gentlemen in attendance were warned not to wear ties since on that day women carrying scissors will cut men’s ties off.

This meeting provided a good overview of the three major study groups (COG, SIOPEN, and GPOH) and comparing and contrasting the approaches they each have taken in treating neuroblastoma, particularly newly diagnosed and relapsed or refractory high risk disease. Some of this information is fairly easy to obtain in published literature, abstracts from major oncology meetings, and clinical trials listings, but learning about current trials in Europe is far more difficult than in the US. Hearing many leading European researchers present on their current work was very enlightening. The meeting was preceded by the “Master Class” and the closed SIOPEN committee spring meeting. The Master Class included an overview of the pathology, staging and risk stratification, surgical and imaging issues, chemotherapy, and immunotherapy strategies for treating neuroblastoma and follow-on sessions addressed some of these topics in more detail.  The rest of the meeting consisted of presentations on current clinical and preclinical work, challenges in validation of “personalized medicine” predictive models, and progress on the genome-wide association studies and TARGET project presented by John Maris (CHOP).

Pathology.  Ivo Leuschner (Kiel, Germany) gave two talks on pathology and showed that although a tremendous body of work has been done in characterizing the complex pathology of neuroblastic tumors and remains important for diagnosis, the pathology is not as important as the genetics for prognosis.

Imaging.  Imaging advances were discussed by Jürgen Schaefer (Tübingen, Germany) in two talks and suggested the potential use for PET/MRI, other tracers and carriers, and anti-GD2 imaging. One question raised about the latter is if neutralizing antibodies could be a problem from this form of imaging and potentially interfere with future anti-GD2 antibody treatment for children who receive this type of imaging.

Roland Bares (Tübingen, Germany) presented on the development and state of the art of I131-MIBG for imaging and radiotherapy, which was first used Tübingen in the 1980s. [1]

Chemotherapy.  Frank Berthold (Cologne, Germany) presented on the various chemotherapy induction regimens developed for high risk neuroblastoma and gave a separate talk on the results of the GPOH trial. The chemotherapy agents, combinations, timing, and number of cycles have been varied considerably over the past 30 years, and the consensus is that the response rate cannot be further improved by more dose intensification given the significant toxicities of these regimens. In early studies (NB79 – NB90) 13% of children died due to treatment related toxicity or second malignancy, and in later studies (up to NB97) this rate dropped to 6%. He showed a chart comparing the induction regimens of the three major study groups COG, SIOPEN, and GPOH. The COG is currently using two cycles of topotecan and cyclophosphamide followed by four cycles of previously used alternating combinations, and the GPOH NB2004 (finished accrual but no analysis yet)  randomized adding on topotecan and cyclophoshamide to previously used 6 cycle combination. The SIOPEN uses 8 cycles of time intensive chemotherapy given every 10 days instead of every 21 as in the COG and GPOH. In further analysis of the prior GPOH trials, they found that 22-29% of survivors had no late effects, depending on the era of treatment, and 53% had hearing loss.

Staging. Tom Monclair (Oslo, Norway) discussed the INRGSS (International Neuroblastoma Risk Group Staging System) which separates localized tumors into two groups, L1 and L2, where L1 has no image-defined risk factors. The metastatic disease stages are M and MS (where MS is the same as 4S but the age can go up to 18 months).  Dr Monclair also gave another talk on the INRG risk group stratification system.

Surgery. Michael LaQuaglia (Memorial-Sloan Kettering, NY) presented twice on surgical issues that have been debated over the years, particularly the importance of complete resection and how important surgical reports are for categorizing complete resections.  Jorg Fuchs (Tübingen, Germany) presented on minimally invasive surgical techniques and on abdominal resections, Dietrich von Schweinitz (Munich, German) talked about thoracic tumors, Jan Godzinski (Wroclaw, Poland) discussed thoracic-jugular junction surgeries, and Paul Losty (Liverpool, UK) presented meta-analysis data showing aggressive surgical resections improve survival in stage 3 tumors but not in stage 4 tumors.

Immunotherapy.  Paul Sondel (University of Wisconsin-Madison) was one of the early investigators working on the ch14.18 antibody and he presented a clear overview of the COG ch14.18 (chimeric antibody) and hu14.18-IL2 (humanized antibody with IL2 bound directly to the antibody) results along with the current and future directions.  He showed the significance of KIR/KIR-L (killer-immunoglobulin receptor-ligand) mismatch in the results of the hu14.18-IL2 COG phase II trial [2] and prior evidence of significantly better survival in post-ASCT setting.  [3]

Dr Sondel also discussed future plans for a trial using MIBG therapy, reduced intensity conditioning for haploidentical transplant followed by hu14.18-IL2 and donor NK cells.

Thorsten Simon reviewed the retrospective data on the GPOH NB 90 and NB 97 trials (2004 and 2011 publications showing questionable immediate benefit but statistical long term benefit to ch14.18 without cytokines).

Holger Lode (Griefswald, Germany) has a very active group working on immunotherapy approaches. They reported preclinical work on GD2-specific NK cells, MYCN-DNA vaccine, fenretinide and ch14.18, and current use of ch14.18 with IL2 for relapse. His group has also developed an anti-idiotype antibody called ganglidiomab for the baseline of development of DNA and protein vaccines for future trials.  A similar approach was taken by Alice Yu in a trial with 1A7 [4] and at Memorial-Sloan Kettering with a trial of A1G4. [5]

A “curative” approach for relapsed neuroblastoma?

Professor Berthold went on to describe the German “curative approach for recurrences” which has included new chemotherapy combinations such as RIST (rapamycin, irinotecan, sprycel/dasatinib and temozolomide), MIBG radiation therapy, second autologous stem cell transplant, and now MIBG therapy followed by haploidentical stem cell transplant and ch14.18 immunotherapy with IL2.

RIST

Selim Corbacioglu (Regeburg, Germany) presented preliminary results of notable response rates in a small series of patients who received compassionate use of RIST combination. RIST consists of repeated courses of rapamycin/dasatinib (R/S) for 4 days followed by 5 days of irinotecan/temozolomide (I/T). Eighteen relapsed and 2 refractory children (median age 3 years old with 11 in 1st relapse, 7 in 2nd or greater relapse) received median 16 courses of R/S and 7 I/T courses. After a median of 12 weeks, 18/20 showed clinical benefit with complete response in 12 (60%), partial response in 2/20, and stable disease in 4/20. A large German multi-instituition trial is planned to randomize patients to either irinotecan/temozolomide or RIST and will begin enrolling soon. [6]

Haploidentical stem cell transplant

Peter Lang (Tübingen, Germany) gave a presentation on preliminary results of an ongoing trial treating relapsed neuroblastoma patients with MIBG radiotherapy, haploidentical stem cell transplant, followed by 6 cycles of ch14.18 with IL2. Prior to entering the trial children have disease burden reduced by chemotherapy, surgery, and/or radiation with no disease progression. Those in complete or partial response are eligible for the trial. Professor Lang and his colleagues have treated 60 children with solid tumors with haplo SCTs, and have enrolled 25 NB patients on this trial to date, and 9 patients completed the protocol thus far. There have been no treatment related mortalities and 1 transient graft-versus-host disease. Six of nine of those who have completed the protocol are in complete remission or improved their partial remission, and 3 progressed.[7]

Kenneth DeSantes (University of Wisconsin-Madison) presented early data (4 patients, 2 with NB) on his trial treating pediatric cancers with haplo SCT followed by donor NK cell infusion.  The trial has been modified to reduce the possibility of graft-versus-host disease for subsequent patients. [8]

Another haploidentical transplant trial recently opened at Kansas City by PI Doug Myers, following with tri-virus specific T cells. [9-10]

Recently an interesting case study was reported from France (with Peter Lang as co-author) where a child who relapsed after a haplo SCT had a complete response to a combination of immuno-chemotherapy based on donor NK cells transplants, IL2 infusions and temozolomide/topotecan. [11]

Profound finale

Overall the meeting was very enlightening. As a touching conclusion to the meeting, the organizers introduced a young man (27) who was diagnosed with stage 4 MYCN-amplified disease when he was 3 years old in 1988, treated there at Tübingen.  He relapsed after frontline therapy, had an allogeneic transplant, then relapsed again, and then had a haplo SCT, and was the very first child to receive antiGD2 antibodies. Today he is a doctoral student at the same university.

Nick Bird, Dad to warrior Adam, attended and wrote an excellent piece on the meeting, please see his blog:  http://adamsappeal.blogspot.com/2012/02/tubingen-symposium.html

References:

1. Prog Clin Biol Res. 1988;271:669-78. MIBG-treatment in neuroblastoma; experiences of the Tübingen/Frankfurt group. http://www.ncbi.nlm.nih.gov/pubmed/3406023

2. Cancer Res. 2010 Dec 1;70(23):9554-61. Epub 2010 Oct 8. Genotypes of NK cell KIR receptors, their ligands, and Fcγ receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. http://www.ncbi.nlm.nih.gov/pubmed/20935224

3. Clin Cancer Res. 2009 Dec 1;15(23):7330-4. Epub 2009 Nov 24. KIR and HLA genotypes are associated with disease progression and survival following autologous hematopoietic stem cell transplantation for high-risk neuroblastoma. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788079/

4. ASCO 2010 Education Book Pediatric Cancer: Progress in Treatment of High-risk Neuroblastoma with Immunotherapy.  http://www.asco.org/ASCOv2/Home/Education%20&%20Training/Educational%20Book/PDF%20Files/2010/zds00110000408.pdf

5. Phase I trial to study the effectiveness of monoclonal antibody A1G4 plus BCG in treating patients with cancer. http://clinicaltrials.gov/ct2/show/NCT00003023

6. Study of a Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma (RIST-rNB-2011)  http://clinicaltrials.gov/ct2/show/NCT01467986

7. Phase II Feasibility Study using ch14.18/CHO antibody and IL2 after Haploidential Stem Cell Transplantation in Children with Relapsed Neuroblastoma  http://www.kinder-krebs-forschung.de/wp-content/uploads/Studienmaterial-AK_Studie-englisch1.txt

8. Haploidentical Transplant With NK Cell Infusion for Pediatric Acute Leukemia and Solid Tumors  http://clinicaltrials.gov/ct2/show/NCT00582816

9. Allogeneic Stem Cell Transplantation for Advanced Neuroblastoma Using MHC Mismatched Related Donors (STALLO) http://clinicaltrials.gov/ct2/show/NCT01462396

10. Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma (STALLONe)  http://clinicaltrials.gov/ct2/show/NCT01460901

11. Pediatr Blood Cancer. 2011 Dec 16. doi: 10.1002/pbc.24030. NK Cell immunotherapy for high-risk neuroblastoma relapse after haploidentical HSCT.  http://www.ncbi.nlm.nih.gov/pubmed/22180305